Noise is the most common occupational and environmental hazard, thus it is not surprising that noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, second only to age-related hearing loss. Although therapeutics that target the free radical pathway have shown promise for reducing NIHL, there are no medications approved by the U.S. Food and Drug Administration for NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. Therefore, a new approach is necessary to combat these multiple signaling pathways in order for therapeutics to be successful at preventing and treating NIHL. Recent preclinical studies have demonstrated that calcium channel blockers and anti-inflammatory drugs can prevent NIHL. Tetrandrine (TET), a bis-benzylisoquinoline alkaloid originally purified from a Chinese medicinal herb, shows strong promise as a NIHL therapeutic due to its antioxidant and anti-inflammatory properties, as well as its ability to block calcium channels. Moreover, the use of TET clinically has shown a long-term safety profile. Based on our preliminary findings that TET could protect against NIHL, in this Phase I STTR application, we will determine the median effective dose (ED50) for this drug to prevent (Aim 1) and treat (Aim 2) NIHL in two different animal models. The innovative aspects in our approach for using TET are: (1) TET already has well-characterized pharmacological properties and a long history of clinical applications; and (2) TET is known to intervene in multiple signaling pathways involved in NIHL. We will use the data from these studies to complete an Investigational New Drug (IND)-enabling data package for our SBIR phase II clinical studies of this agent. The goal of this program is to bring TET to market for use in prevention and treatment of NIHL.